Palladium-catalyzed synthesis of 2-alkenyl-3-arylindoles via a dual α-arylation strategy: Formal synthesis of the antilipemic drug fluvastatin

Article abstract of DOI:10.1039/c5ob01632k

A new approach has been developed for the synthesis of substituted 2-alkenyl-3-arylindoles. The strategy comprises palladium-catalyzed dual α-arylation of TES-enol ethers of enones as the key step. This methodology results in products with very good yields and the regioselectivity is exclusive. We have also successfully used this dual α-arylation methodology in the formal synthesis of the cholesterol-lowering drug fluvastatin.

Full text of DOI:10.1039/c5ob01632k

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Palladium-catalyzed synthesis of 2-alkenyl-
3-arylindoles via a dual α-arylation strategy:
formal synthesis of the antilipemic drug
fluvastatin†
Cite this: DOI: 10.1039/c5ob01632k
Ajit Prabhakar Kale, Gangam Srikanth Kumar and Manmohan Kapur*
Received 5th August 2015,
Accepted 9th September 2015
A new approach has been developed for the synthesis of substituted 2-alkenyl-3-arylindoles. The strategy
comprises palladium-catalyzed dual α-arylation of TES-enol ethers of enones as the key step. This methodo-
logy results in products with very good yields and the regioselectivity is exclusive. We have also successfully
used this dual α-arylation methodology in the formal synthesis of the cholesterol-lowering drug fluvastatin.
DOI: 10.1039/c5ob01632k
www.rsc.org/obc
This biologically important molecule incorporates a 2-alkenyl-
3-aryl indole core.
Introduction
Indoles belong to an important class of nitrogen heterocycles.
Our laboratory has been engaged in the synthesis of func-
Several biologically active natural as well as synthetic products, tionalized nitrogen heterocycles,3 and in particular the regio-
important materials, contain the indole core structure. By selective synthesis of 2-alkenylindoles and carbazoles3b via
virtue of being a part of the essential amino acid tryptophan, palladium catalyzed α-arylation of triethylsilyl enol ethers of
the indole skeleton is a component of several peptide-based enones4 (Scheme 1). This method provides an alternative
natural products too.1 Due to the critical role of indole based approach to the oxidative-Heck reaction of indoles which is
compounds in human life, synthesis of the indole core and its usually employed for the synthesis of 2-alkenylindoles.
functionalization have received great attention from synthetic
We chose fluvastatin (Fig. 1) as a potential target since it
chemists all over the world. Ever since the first synthesis of presented us with a challenge to synthesize the 2-alkenyl-3-
indoles by Fischer and Jourdan, using aryl hydrazones,1a syn- arylindole core using our method. To the best of our knowl-
thetic approaches to indoles have come a long way and various edge there is neither any conventional method for the syn-
approaches have been reported for the synthesis of the ubiqui- thesis of 2-alkenyl-3-arylindoles from o-haloanilines and
tous indole nucleus.1
enones nor is there a report for C-3 arylation of 2-alkenylin-
Fluvastatin (Fig. 1) is a synthetic molecule which belongs to doles. Lee and co-workers reported the synthesis of 2-alkenyl-
an important class of statin drugs. Statins act as hydroxy- 3-arylindoles from C-3 aryl indoles via an alkenylation reac-
methylglutaryl-coenzyme A reductase (HMG-CoA reductase) tion.5a Prasad and co-workers used a Horner–Wadsworth–
inhibitors and bring down the cholesterol level in the body.2 Emmons reaction to generate the 2-alkenyl-3-arylindoles.5b
Therefore there was a need to develop a new method for the
synthesis of highly functionalized 2-alkenyl-3-arylindoles
which could be applied in the synthesis of fluvastatin and its
analogs. The method could then be generalized for the syn-
thesis of several important building blocks containing the
2-alkenyl-3-arylindole moiety. The development of such a
method would also help in achieving a general approach for a
Fig. 1 Fluvastatin: an antilipemic drug molecule.
Department of Chemistry, Indian Institute of Science Education and Research
Bhopal, Academic Building II, Bhopal Bypass Road, Bhauri, Bhopal 462066, MP,
India. E-mail: mk@iiserb.ac.in
†Electronic supplementary information (ESI) available: Copies of NMR spectra
Scheme 1 Synthesis of 2-alkenylindoles and carbazoles using the
α-arylation approach.
of new compounds and important intermediates. See DOI: 10.1039/c5ob01632k
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library of fluvastatin analogs which could be helpful in study-
ing structure activity relationships.
Table 1 Dual application of the α-arylation strategy in the synthesis of
2-alkenyl indolesa
Results and discussion
Towards the synthesis of this important building block, we
initially attempted the transition-metal catalyzed C-3 arylation
of 2-alkenyl indoles by using various aryl halides or aryl
boronic acids but the efforts did not meet much success.1k,6
We then envisioned that the α-arylation strategy for silylenol
ethers of enones3b could be easily utilized in the synthesis of
the desired 2-alkenyl-3-aryl indoles. Using this method, we
first synthesized α-aryl enones4a which were then subjected to
enolization to generate the corresponding triethyl silyl enol
ethers. These, when subjected to the previously standardized
conditions,3b reacted very well with o-bromoanilines, when
using xylene as a solvent at 120 °C. The 2-alkenyl-3-arylindoles
were obtained as the exclusive products (Table 1).
This approach represents one of the shortest intermolecular
annulation approaches for this class of densely substituted
indoles. Also, it constitutes one of the rare instances where the
same key step has been employed twice in the assembly of an
important class of compounds of the indole family.
As from our previous experience,3b we observed higher
yields with N-alkyl o-haloanilines and slightly lower yields with
free –NH o-haloanilines. To obtain the compounds 5o, 5p
(Table 1), we employed 1-acetyl cyclohexene instead of simple
aliphatic enones. The reaction was found to be quite general
in terms of substrate scope and variations in anilines and the
enones worked very well. It was encouraging to see that
o-bromoanilines substituted with electron-donating as well as
electron-withdrawing groups gave the desired products in good
yields (Table 1, entries 5g, 5i, and 5j). A variety of α-aryl enones
were also screened for the annulation reaction and the reac-
tion was found to be quite general. As observed earlier too, we
obtained a minor side product, which was formed due to
homocoupling of o-bromoanilines.3b,7 Also, the reaction did
not result in clean transformations when ortho-substituted aryl
halides or arylboronic acids were employed.4a
a All yields mentioned are for the second arylation and are isolated
yields. DtBPF = Di-tert-butylphosphino ferrocene.
As fluvastatin is an important drug molecule, various syn-
thetic strategies aimed at the construction of such statins have
been reported.8 All known approaches to fluvastatin begin with
the indole moiety which is functionalized first at C-2 and C-3 resulted in isomerization of Z-olefin to the more stable
E-isomer. The enone 11 was converted into its silylenol ether
14 and arylated with 4-fluorobromobenzene to form the α-ary-
carbon centers, followed by enantioselective transformations
to complete the synthesis of the side chain.5,8 We came up
with a different approach for the formal synthesis of fluvasta- lated enone 9 in 55% yield.4a This first arylation product was
then subjected to enolization conditions, followed by the palla-
tin (6), in which we envisioned that the C-2-alkenyl-C-3-aryl-
indole moiety could be formed in one step by the α-arylation
dium-catalyzed α-arylation to yield the indole product 5k in
reaction of triethylsilylenol ether of enone (9) with 2-bromo-N- 71% yield.3b Deprotection of the O-trityl group followed by a
mild oxidation led to the aldehyde 7 (12 : 1 mixture of E : Z
olefin isomers). The use of other oxidizing agents led to rapid
isopropyl aniline (8) (Scheme 2). The precursor to this enone
could be achieved via the α-arylation of enone (11), which in
turn could be synthesized from the commercially available decomposition of the resulting aldehyde 7. The synthesis of
this aldehyde 7 constituted the formal synthesis of fluvastatin
(6). The further steps are well documented in the literature, by
starting material cis-2-butene-1,4-diol (12).
O-Trityl protected enone 11 9 was easily synthesized from
cis-2-butene-1,4-diol (12) (Scheme 3). The oxidation step Hayashi and co-workers.8b
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cation in the assembly of very useful scaffolds and can be used
in the synthesis of more densely functionalized building
blocks.
Experimental
General methods
All commercially available compounds (Acros, Aldrich, Fluka,
Merck etc.) were used without purification. Unless otherwise
noted, all reactions were performed in oven-dried glassware.
All reactions were run under an argon or nitrogen atmosphere.
All solvents used in the reactions were purified before use.
Tetrahydrofuran, dioxane, and toluene were distilled from
sodium and benzophenone, whereas dichloromethane, di-
methylformamide and triethylamine were distilled from
CaH2.10 Petroleum ether with a boiling range of 40–60 °C was
used. Melting points are uncorrected. 1H and 13C NMR:
recorded on a Bruker Avance III 400 MHz NMR spectrometer
and a Bruker Avance III 500 MHz NMR spectrometer; spectra
were recorded at 295 K in CDCl3; chemical shifts are calibrated
to the residual proton and carbon resonance of the solvent:
CDCl3 (1H δ 7.25; 13C δ 77.0). HRMS: Bruker Daltonics
MicroTOF-Q-II with electron spray ionization (ESI) or atmo-
spheric pressure chemical ionization (APCI). GC-HRMS: per-
formed on Agilent 7200 GC-QToF (with Electron Impact (EI),
70 eV) with 7890A GC using the DB-5 column. GC-LRMS: per-
formed on Agilent 7890A GC with Agilent 5975C MS (EI 70 eV)
using the DB-5 column. IR: Perkin Elmer spectrum BX FTIR,
Shimadzu IRAffinity-1 FTIR and were recorded as thin films
between KBr plates.
Scheme 2 Retrosynthetic analysis of fluvastatin.
General procedures
General procedure for the synthesis of N-methyl-o-haloani-
line.11 o-Haloaniline (10 mmol, 2 eq.) was dissolved in THF
(10 mL). A solution of n-BuLi (1.6 M in hexane, 5 mmol,
1.0 eq.) was added slowly at −40 °C and the resulting red
mixture was stirred for 15 min at the same temperature. After
cooling to −60 °C, iodomethane (5 mmol, 1.0 eq.) was added
slowly and the mixture was allowed to warm to RT and stirred
for an additional 14 h at RT. The reaction mixture was
quenched by adding H2O and the organic phase was separ-
ated. The aqueous phase was extracted with EtOAc and the
combined organic phases were washed with sat. NaHCO3 solu-
tion, dried over Na2SO4 and the solvents were evaporated
under reduced pressure. The product was purified by silica gel
flash column chromatography.
Scheme 3 Formal synthesis of fluvastatin: dual application of the
α-arylation strategy.
General procedure for the synthesis of N-isopropyl-o-halo-
aniline. o-Haloaniline (10 mmol, 1 eq.) was dissolved in DMF
(10 mL) and the resulting solution was cooled to 0 °C. To this
was added NaH (20 mmol, 2 eq.) slowly at 0 °C and the result-
ing mixture was stirred for 15 min at the same temperature,
followed by a slow addition of isopropyl iodide (15 mmol,
1.5 eq.). The mixture was allowed to warm to RT and stirred for
an additional 12 h. The reaction was quenched by adding H2O
and the organic phase was separated. The aqueous phase was
Conclusions
In summary, we have developed a novel intermolecular annula-
tion strategy, for the short and quick synthesis of 2-alkenyl-3-
arylindoles and its efficacy was demonstrated in the formal
synthesis of fluvastatin. In doing so, we have successfully
employed the key α-arylation methodology twice in achieving
the synthesis of this important scaffold. The substrate scope is
very good and the method is expected to have broad appli-
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extracted with EtOAc (3 × 30 mL) and the combined organic 6H), 6.86 (d, J = 15.8 Hz, 1H), 6.73 (d, J = 15.8 Hz, 1H), 5.88 (s,
phases were washed with satd NaHCO3 solution, dried over 1H), 0.96 (t, J = 7.9 Hz, 9H), 0.66 (q, J = 7.9 Hz, 6H); 13C NMR
anhyd. Na2SO4 and the solvent was removed under reduced (100 MHz, CDCl3) δ 150.4, 136.9, 136.5, 128.9, 128.8, 128.7,
pressure. The product was purified by silica gel flash column 128.1, 128.1, 127.6, 126.6, 126.3, 114.9, 6.9, 5.5; APCI-HRMS:
chromatography.
Calculated for C22H29OSi [M + H]+ 337.1982, found 337.1994.
General procedure for the synthesis of triethylsilyl (TES)
Triethyl(((1E,3E,5E)-1-phenylhepta-1,3,5-trien-2-yl)oxy)silane
enol ethers of enones.4a A solution of diisopropylamine (3b). Yield: (758 mg, 68%); physical appearance: colorless oil;
(1.83 mL, 13.0 mmol) in dry THF (26 mL) was cooled to TLC (neutral alumina) Rf 0.75 (petroleum ether); IR (KBr,
−78 °C. To this was added n-BuLi dropwise (8.12 mL, cm−1): 3069, 1609, 1482, 1303, 976, 790; 1H NMR (400 MHz,
13.0 mmol, 1.6 M in hexanes). The reaction mixture was CDCl3) δ 7.57–7.47 (d, J = 7.7 Hz, 2H), 7.27 (t, J = 7.7 Hz, 2H),
stirred for 30 min at −78 °C. To this stirring solution of LDA in 7.17–7.10 (m, 1H), 6.48 (dd, J = 15.1, 10.8 Hz, 1H), 6.20–6.09
THF, was added dropwise, a solution of the enone (10.0 mmol) (m, 1H), 6.05 (d, J = 15.2 Hz, 1H), 5.85–5.74 (m, 1H), 5.71 (s,
in dry THF (5 mL) over a period of 10 min. After the solution 1H), 1.81 (dd, J = 6.9, 1.6 Hz, 3H), 0.93 (t, J = 7.9 Hz, 9H), 0.61
was stirred for 30 min at −78 °C, TES-Cl (2.18 mL, 13.0 mmol) (q, J = 7.9 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 13C NMR
was added. The mixture was stirred at that temperature for an (100 MHz, CDCl3) δ 150.4, 136.7, 131.2, 130.7, 129.71, 129.1,
additional 30 min following which it was then slowly warmed 128.7, 127.9, 125.9, 113.5, 18.4, 6.7, 5.4; APCI-HRMS: Calcu-
to room temperature and stirred for another hour. The reac- lated for C19H28OSi [M + Na]+ 323.1802, found 323.1806.
tion mixture was then quenched with 2 mL ice-cold, saturated
Triethyl(((1E,3E)-1-(4-fluorophenyl)-4-phenylbuta-1,3-dien-2-yl)-
aq. NaHCO3. After dilution with hexanes (100 mL), the mixture oxy)silane (3c). Yield: (575 mg, 67%); physical appearance:
was washed with cold saturated NaHCO3 solution. The organic colorless oil; TLC (neutral alumina) Rf 0.75 (petroleum ether);
1
extract was dried over anhyd. Na2SO4, filtered and concen- IR (KBr, cm−1): 3025, 1452, 1028, 906, 770; H NMR (400 MHz,
trated under reduced pressure. The crude oil was purified by CDCl3): δ 7.62–7.54 (m, 2H), 7.49–7.47 (m, 2H), 7.37 (t, J =
neutralized silica gel column chromatography (eluting with 7.4 Hz, 2H), 7.30–7.25 (m, 1H), 7.08–6.93 (m, 2H), 6.88 (d, J =
hexane) to provide the desired enol ether.
16 Hz, 1H), 6.73 (d, J = 16 Hz, 1H), 5.86 (s, 1H), 0.99 (t, J =
General procedure for the synthesis of triethylsilyl (TES) 8.0 Hz, 9H), 0.69 (q, J = 7.9 Hz, 6H); 19F NMR (376 MHz,
enol ethers of enones.4a TESOTf (1.70 mL, 7.52 mmol) was CDCl3): δ −115.15; 13C NMR (100 MHz, CDCl3): δ 161.3 (d,
added dropwise to a pre-cooled (−10 °C) stirring solution of JC–F = 246.3 Hz), 150.2 (d, JC–F = 1.9 Hz), 136.9, 132.7 (d, J C–F
=
enone (6.84 mmol) and triethylamine (1.45 mL, 10.26 mmol) 3.3 Hz), 130.5 (d, JC–F = 7.7 Hz), 128.9, 128.8, 128.2, 127.9 (d,
in dry CH2Cl2 (25 mL). After 15 min, the solution was poured JC–F = 16.3 Hz), 126.6, 115.2 (d, JC–F = 21.2 Hz), 113.7, 6.8, 5.5;
into saturated aqueous NaHCO3 and extracted with DCM. The APCI-HRMS: Calculated for C22H28FOSi [M + H]+ 355.1888,
organic layer was dried (anhydrous Na2SO4), filtered and con- found 355.1890.
centrated under reduced pressure. The residue was purified by
(((1E,3E)-1-(4-(tert-Butyl)phenyl)-4-phenylbuta-1,3-dien-2-yl)oxy)-
neutralized silica gel column chromatography (eluting with triethylsilane (3d). Yield: (682 mg, 69%); physical appearance:
hexanes) to provide the desired product.
colorless oil; TLC (neutral alumina) Rf 0.75 (petroleum ether);
General procedure for synthesis of 2-alkenyl-3-arylindoles IR (KBr, cm−1): 3021, 1610, 1402, 1300, 790; 1H NMR
from TES enol ethers of α-arylenones and o-haloaniline.3b In a (400 MHz, CDCl3) δ 7.56 −7.49 (m, 2H), 7.45 (d, J = 7.4 Hz,
pressure tube equipped with
a stir bar, o-haloaniline 2H), 7.39–7.30 (m, 5H), 7.28–7.22 (m, 2H), 6.84 (d, J = 15.8 Hz,
(0.5 mmol) and TES-enol ether of enone (0.7 mmol) in dry 1H), 6.73 (d, J = 15.8 Hz, 1H), 5.87 (s, 1H), 1.34 (s, 9H),
xylene (2 mL) were taken. The reaction mixture was degassed 0.97 (t, J = 7.9 Hz, 9H), 0.68 (q, J = 7.9 Hz, 6H); 13C NMR
for 10 min followed by the addition of Pd(OAc)2 (0.025 mmol), (100 MHz, CDCl3) δ 149.9, 149.4, 137.1, 133.6, 128.9, 128.7,
DtBPF (0.050 mmol), CsF (0.7 mmol) and Bu3SnF (0.7 mmol). 128.6, 128.3, 127.5, 126.6, 124.9, 114.9, 34.6, 31.4, 6.8, 5.5.
The tube was fitted with a Teflon screw cap under an argon APCI-HRMS: Calculated for C26H37OSi [M + H]+ 393.2608,
flow. The reaction mixture was heated to 120 °C and allowed to found 393.2635.
stir at that temperature for 2–4 h. Upon cooling to room temp-
(((1E,3E)-1-(3,5-Dimethylphenyl)-4-phenylbuta-1,3-dien-2-yl)oxy)-
erature, the reaction mixture was diluted with about 10 mL of triethylsilane (3e). Yield: (365 mg, 77%); physical appearance:
diethyl ether and the resulting slurry mixture was filtered colorless liquid; TLC Rf 0.8 (petroleum ether); this compound
through a pad of Celite. The filtrate was extracted with diethyl was used immediately upon work-up. 1H NMR (400 MHz,
ether and washed successively with 1 M NaOH and water. After CDCl3): δ 7.49–7.43 (m, 2H), 7.39–7.33 (m, 2H), 7.29–7.22 (m,
concentration of the organic extract under reduced pressure, 3H), 6.89–6.82 (m, 2H), 6.73 (d, J = 15.9 Hz, 1H), 5.84 (s, 1H),
the crude product was purified by a silica gel column 2.33 (s, 6H), 0.99 (t, J = 7.9 Hz, 9H), 0.70 (q, J = 7.9 Hz, 6H).
chromatography.
(Z)-((1-(Cyclohex-1-en-1-yl)-2-(3-nitrophenyl)vinyl)oxy)triethyl-
(((1E,3E)-1,4-Diphenylbuta-1,3-dien-2-yl)oxy)triethylsilane (3a). silane (3f). Yield: (611 mg, 69%); physical appearance: color-
Yield: (1.2 g, 67%); physical appearance: colorless oil; TLC less liquid; TLC Rf 0.65 (petroleum ether); this compound was
(neutral alumina) Rf 0.75 (petroleum ether); IR (KBr, cm−1): also used immediately upon work-up.
1
3059, 1609, 1492, 1373, 906, 790; H NMR (400 MHz, CDCl3)
(Z)-((2-(4-(tert-Butyl)phenyl)-1-(cyclohex-1-en-1-yl)vinyl)oxy)tri-
δ 7.58 (d, J = 7.2 Hz, 2H), 7.45 (d, J = 7.2 Hz, 2H), 7.39–7.15 (m, ethylsilane (3g). Yield: (575 mg, 71%); physical appearance:
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colorless liquid; TLC Rf 0.75 (petroleum ether); this compound (s, 3H), 1.80 (d, J = 6.8 Hz, 3H), 1.68 (d, J = 7.0 Hz, 6H);
was also used immediately upon work-up.
13C NMR (100 MHz, CDCl3): δ 135.9, 134.9, 134.4, 133.9, 132.0,
1,5-Dimethyl-2-((1E,3E)-penta-1,3-dien-1-yl)-3-phenyl-1H-indole 130.8, 130.4, 128.9, 128.8, 128.3, 125.8, 123.2, 119.2, 119.1,
(5a). Yield: (125 mg, 87%); physical appearance: white solid; 115.5, 111.5, 47.6, 21.7, 21.4, 18.3; IR (KBr, cm−1): 3026, 2934,
m. p. 96–98 °C; TLC Rf 0.5 (9 : 1 petroleum ether : EtOAc); 1608, 1498, 1141, 988; ESI-HRMS: Calculated for C23H25N [M]+
IR (KBr, cm−1): 3029, 2937, 1589, 1489, 1461, 1201, 989; 1H 315.1982, found 315.1999.
NMR (400 MHz, CDCl3): δ 7.51–7.41 (m, 4H), 7.37 (s, 1H),
1-Isopropyl-2-((1E,3E)-penta-1,3-dien-1-yl)-3-phenyl-1H-indole
7.32–7.26 (m, 1H), 7.20 (d, J = 8.4 Hz, 1H), 7.05 (dd, J = 8.3, 1.7 (5f). Yield: (122 mg, 82%); physical appearance: off-white
Hz, 1H), 6.53–6.44 (m, 2H), 6.23–6.10 (m, 1H), 5.74–5.64 (m, solid; mp 96–100 °C; TLC Rf 0.6 (20 : 1 petroleum ether :
1H), 3.80 (s, 3H), 2.40 (s, 3H), 1.78 (dd, J = 6.9, 1.7 Hz, 3H); 13
C
EtOAc); IR (KBr, cm−1): 3025, 2924, 1601, 1492, 1451, 1181,
NMR (100 MHz, CDCl3): δ 136.5, 135.7, 134.4, 133.2, 132.4, 990; 1H NMR (400 MHz, CDCl3): δ 7.63 (d, J = 8.0 Hz, 1H), 7.56
130.6, 130.3, 129.3, 128.4, 127.5, 126.0, 124.0, 118.9, 118.8, (d, J = 8.0 Hz, 1H), 7.54–7.48 (m, 2H), 7.47–7.40 (m, 2H),
115.9, 108.9, 31.4, 21.4, 18.4; GC-HRMS: Calculated for 7.34–7.27 (m, 1H), 7.23–7.16 (m, 1H), 7.14–7.06 (m, 1H), 6.50
C21H21N [M]+ 287.1669, found 287.1673.
(d, J = 15.0 Hz, 1H), 6.37–6.12 (m, 2H), 5.77–5.56 (m, 1H),
(E)-1-Isopropyl-3-phenyl-2-styryl-1H-indole (5b). Yield: (144 mg, 5.00–4.85(m, 1H), 1.80 (d, J = 6.8 Hz, 3H), 1.69 (d, J = 7.0 Hz,
86%); physical appearance: off-white solid; mp 135–138 °C; 6H); 13C NMR (100 MHz, CDCl3): δ 135.8, 135.6, 135.3, 134.3,
TLC Rf 0.6 (20 : 1 petroleum ether : EtOAc); IR (KBr, cm−1): 131.9, 131.0, 130.4, 128.6, 128.4, 125.9, 121.6, 119.7, 119.6,
3025, 1601, 1491, 1181, 1028; 1H NMR (400 MHz, CDCl3): 118.9, 115.8, 111.8, 47.6, 21.7, 18.3; GC-HRMS: Calculated for
δ 7.65 (d, J = 8.0 Hz, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.55–7.48 (m, C22H23N [M + Na]+ 324.1723, found 324.1720.
2H), 7.46–7.25 (m, 8H), 7.23–7.06 (m, 3H), 6.64 (d, J = 16.5 Hz,
(E)-3-(4-(tert-Butyl)phenyl)-1-isopropyl-5-nitro-2-styryl-1H-indole
1H), 5.11–4.92 (m, 1H), 1.71 (d, J = 7.0 Hz, 6H); 13C NMR (5g). Yield: (177 mg, 81%); physical appearance: white solid;
(100 MHz, CDCl3): δ 137.2, 135.8, 135.6, 134.5, 134.1, 130.4, mp 235–237 °C; TLC Rf 0.5 (9 : 1 petroleum ether : EtOAc);
128.7, 128.5, 128.4, 127.9, 126.4, 126.0, 121.9, 119.8, 119.7, IR (KBr, cm−1): 3015, 2841, 1612, 1475, 1201, 990; 1H NMR
118.1, 111.9, 47.8, 21.8; APCI-HRMS: Calculated for C25H24N (400 MHz, CDCl3): δ 8.56 (d, J = 2.4 Hz, 1H), 8.09 (dd, J = 9.2,
[M + H]+ 338.1903, found 338.1907.
2.3 Hz, 1H), 7.57 (d, J = 9.2 Hz, 1H), 7.47 (d, J = 8.3 Hz, 2H),
(E)-1-Isopropyl-5-methyl-3-phenyl-2-styryl-1H-indole (5c). Yield: 7.44–7.32 (m, 6H), 7.32–7.26 (m, 1H), 7.09 (d, J = 16.0 Hz, 1H),
(136 mg, 78%); physical appearance: off-white solid; mp 6.71 (d, J = 16.0 Hz, 1H), 5.07–4.96 (m, 1H), 1.73 (d, J = 7.0 Hz,
127–130 °C; TLC Rf 0.6 (20 : 1 petroleum ether : EtOAc); 6H), 1.38 (s, 9H); 13C NMR (100 MHz, CDCl3): δ 149.8, 141.6,
IR (KBr, cm−1): 2924, 1601, 1492, 1451, 1181, 990; 1H NMR 138.5, 137.0, 136.64, 136.3, 130.7, 129.7, 128.8, 128.4, 128.1,
(400 MHz, CDCl3): δ 7.56–7.49 (m, 2H), 7.47 (d, J = 8.5 Hz, 1H), 126.6, 125.8, 118.5, 117.3, 117.2, 117.0, 111.3, 48.4, 34.6, 31.4,
7.45–7.36 (m, 5H), 7.36–7.21 (m, 4H), 7.13 (d, J = 16.5 Hz, 1H), 21.8; ESI-HRMS: Calculated for C29H30N2O2 [M
7.04 (d, J = 8.3 Hz, 1H), 6.63 (d, J = 16.5 Hz, 1H), 5.07–4.89 (m, 461.2199, found 461.2224.
+
Na]+
1H), 2.42 (s, 3H), 1.70 (d, J = 7.1 Hz, 6H); 13C NMR (100 MHz,
(E)-3-(4-Fluorophenyl)-1,5-dimethyl-2-styryl-1H-indole (5h). Yield:
CDCl3): δ 137.3, 135.8, 134.2, 134.2, 134.1, 130.4, 129.1, 128.7, (136 mg, 80%); physical appearance: white solid; mp
128.7, 128.4, 127.9, 126.3, 125.9, 123.5, 119.4, 118.2, 116.2, 125–128 °C; TLC Rf 0.5 (19 : 1 petroleum ether : EtOAc);
111.6, 47.8, 21.8, 21.4; ESI-HRMS: Calculated for C26H26N IR (KBr, cm−1): 2934, 1623, 1503, 1464, 1179, 993; 1H NMR
[M + H]+ 352.2060, found 352.2065.
(400 MHz, CDCl3): δ 7.44–7.38 (m, 2H), 7.35–7.23 (m, 5H),
(E)-3-(4-Fluorophenyl)-1-isopropyl-2-styryl-1H-indole (5d). Yield: 7.20–7.16 (m, 2H), 7.11–7.00 (m, 4H), 6.74 (d, J = 16.0 Hz, 1H),
(148 mg, 84%); physical appearance: off-white solid; mp 3.82 (s, 3H), 2.36 (s, 3H); 19F NMR (376 MHz, CDCl3):
110–115 °C; TLC Rf 0.6 (20 : 1 petroleum ether : EtOAc); 1H δ −116.56; 13C NMR (100 MHz, CDCl3): δ 161.6 (d, JC–F
=
NMR (400 MHz, CDCl3): δ 7.59–7.53 (m, 2H), 7.49–7.42 (m, 245.0 Hz), 137.3, 136.6, 134.3, 132.6, 131.7 (d, JC–F = 7.9 Hz),
2H), 7.39–7.30 (m, 4H), 7.28–7.25 (m, 1H), 7.23–7.17 (m, 1H), 131.5, 129.6, 128.8, 127.9, 127.4, 126.3, 124.5, 118.8,
7.14–7.04 (m, 4H), 6.61 (d, J = 16.5 Hz, 1H), 5.04–4.90 (m, 1H), 117.6, 115.6, 115.5 (d, JC–F = 21.3 Hz), 109.1, 31.5, 21.5;
1.70 (d, J = 7.0 Hz, 6H); 19F NMR (376 MHz, CDCl3): δ −116.82; GC-HRMS: Calculated for C24H21FN [M + H]+ 342.1653,
13C NMR (100 MHz, CDCl3): δ 160.24 (d, JC–F = 244.5 Hz), found 342.1661.
137.0, 135.6, 134.8, 134.2, 131.8 (d, JC–F = 7.9 Hz), 131.5 (d, JC–F
(E)-5,7-Difluoro-1-isopropyl-3-phenyl-2-styryl-1H-indole (5i). Yield:
= 3.6 Hz), 128.8, 128.5, 128.0, 126.3, 121.9, 119.8, 119.5, 117.8, (138 mg, 74%); physical appearance: white solid; mp
115.4 (d, JC–F = 21.2 Hz), 115.4, 111.8, 47.8, 21.8; IR (KBr, 148–151 °C; TLC Rf 0.5 (9 : 1 petroleum ether : EtOAc); IR (KBr,
1
cm−1): 2923, 1602, 1455, 1022, 798; APCI-HRMS: Calculated for cm−1): 2944, 1598, 1501, 1451, 1209, 981; H NMR (400 MHz,
C25H23FN [M + H]+ 356.1809, found 356.1824.
CDCl3): δ 7.41–7.25 (m, 8H), 7.23–7.17 (m, 2H), 7.04–6.95 (m,
1-Isopropyl-5-methyl-2-((1E,3E)-penta-1,3-dien-1-yl)-3-phenyl-1H- 2H), 6.72–6.63 (m, 1H), 6.58 (d, J = 16.0 Hz, 1H), 5.03–4.90 (m,
indole (5e). Yield: (130 mg, 83%); physical appearance: off- 1H), 1.61–1.50 (m, 6H); 19F NMR (376 MHz, CDCl3): δ −122.22,
white solid; mp 92–95 °C; TLC Rf 0.6 (20 : 1 petroleum ether : −122.23; 13C NMR (176 MHz, CDCl3): δ 157.1 (dd, JC–F = 237.5,
1
EtOAc); H NMR (400 MHz, CDCl3): δ 7.55–7.38 (m, 6H), 7.31 11.0 Hz), 148.2 (dd, JC–F = 247.1, 13.4 Hz), 137.5, 136.7, 135.9,
(t, J = 7.4 Hz, 1H), 7.09–6.98 (m, 1H), 6.48 (d, J = 15.5 Hz, 1H), 134.7, 130.2, 128.8, 128.7, 128.6, 128.5, 128.4, 128.28, 128.25,
6.35–6.13 (m, 2H), 5.80–5.56 (m, 1H), 4.98–4.81 (m, 1H), 2.42 126.5, 117.5, 100.9–99.5 (m), 99.3–97.9 (m), 48.9, 22.4 (d, JC–F
=
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7.5 Hz); GC-HRMS: Calculated for C25H22F2N [M + H]+
374.1715, found 374.1727.
(E)-3-Phenyl-2-styryl-1H-indole (5n).12 Yield: (83 mg, 56%);
physical appearance: white solid; mp 98–100 °C; TLC
(E)-3-(3,5-Dimethylphenyl)-5,7-difluoro-1-isopropyl-2-styryl-1H- Rf 0.5 (9 : 1 petroleum ether : EtOAc); IR (KBr, cm−1): 3015,
indole (5j). Yield: (142 mg, 71%); physical appearance: white 1643, 1488, 1473, 1221, 990; 1H NMR (400 MHz, CDCl3): δ 8.32
solid; mp 96–98 °C; TLC Rf 0.5 (9 : 1 petroleum ether : EtOAc); (s, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.60–7.54 (m, 2H), 7.50 (t, J =
IR (KBr, cm−1): 2355, 1723, 1687, 1587, 1499, 1445, 1265, 1080, 7.6 Hz, 2H), 7.45 (d, J = 7.3 Hz, 2H), 7.42–7.29 (m, 4H),
748; 1H NMR (500 MHz, CDCl3): δ 7.45–7.36 (m, 4H), 7.34–7.29 7.28–7.22 (m, 3H), 7.13 (t, J = 7.5 Hz, 1H), 6.92 (d, J = 16.6 Hz,
(m, 1H), 7.14–7.08 (m, 4H), 6.99 (d, J = 1.9 Hz, 1H), 6.81–6.75 1H); 13C NMR (100 MHz, CDCl3): δ 137.0, 136.5, 134.5, 132.5,
(m, 1H), 6.73 (d, J = 16.0 Hz, 1H), 5.14–5.01 (m, 1H), 2.37 (s, 130.1, 128.8, 128.7, 128.2, 127.7, 127.3, 126.6, 126.4, 123.6,
6H), 1.72–1.62 (m, 6H); 19F NMR (376 MHz, CDCl3): δ −122.03, 120.5, 119.8, 118.9, 118.0, 110.7.
−122.02; 13C NMR (126 MHz, CDCl3): δ 157.0 (dd, JC–F = 237.4,
3-(4-(tert-Butyl)phenyl)-2-(cyclohex-1-en-1-yl)-5,7-difluoro-1-iso-
11.1 Hz), 148.2 (dd, JC–F = 246.8, 13.6 Hz), 138.0, 137.4, 136.9, propyl-1H-indole (5o). Yield: (164 mg, 81%); physical appear-
135.4, 134.9–134.1 (m), 132.2–131.4 (m), 128.8, 128.3, 128.1, ance: pale-yellow gel; TLC Rf 0.6 (20 : 1 petroleum
127.9, 126.5, 120.6 (d, J = 10.9 Hz), 117.8, 117.6–116.9 (m), ether : EtOAc); IR (KBr, cm−1): 3155, 2970, 1611, 1495, 1393,
100.3 (dd, JC–F = 23.1, 3.8 Hz), 98.8–97.6 (m), 48.8, 22.4 (d, 1108, 992; 1H NMR (400 MHz, CDCl3): δ 7.48–7.36 (m, 4H),
JC–F = 7.6 Hz), 21.4; GC-HRMS: Calculated for C27H26F2N 7.23–7.15 (dd, J = 9.3, 2.4 Hz, 1H), 6.81–6.64 (m, 1H), 5.97–5.81
[M + H]+ 402.2028, found 402.2031.
(m, 1H), 4.87–4.66 (m, 1H), 2.27–2.18 (m, 2H), 2.16–2.08 (m,
(E)-3-(4-Fluorophenyl)-1-isopropyl-2-(3-(trityloxy)prop-1-en-1-yl)- 2H), 1.78–1.165 (m, 2H), 1.61–1.57 (m, 6H), 1.39 (s, 9H);
1H-indole (5k). Yield: (198 mg, 71%); physical appearance: off- 19F NMR (376 MHz, CDCl3): δ −123.00, −123.01; 13C NMR
white solid; mp 142–150 °C; TLC Rf 0.6 (20 : 1 petroleum ether : (100 MHz, CDCl3): δ 156.9 (dd, JC–F = 236.4 Hz), 148.6, 147.2
1
EtOAc); IR (KBr, cm−1): 3059, 1607, 1498, 1154, 1068, 990; H (dd, JC–F = 246.33, 13.26) 143.0, 133.2, 131.9, 131.6 (dd, JC–F
=
NMR (400 MHz, CDCl3): δ 7.55 (t, J = 9.0 Hz, 2H), 7.50–7.39 (m, 10.9, 7.6 Hz), 130.1, 128.6, 125.1, 118.7 (d, JC–F = 10.5 Hz),
8H), 7.34–7.22 (m, 10H), 7.21–7.16 (m, 1H), 7.14–7.05 (m, 3H), 113.6 (q, JC–F = 1.8 Hz)10.1, (dd, JC–F = 23.5, 3.5 Hz), 97.2 (dd,
6.82 (d, J = 16.0, 1H), 5.82 (dt, J = 16.0 Hz, 5.0 Hz, 1H), JC–F = 29.60, 25.56 Hz), 34.5, 31.4, 30.1, 25.6, 22.8, 22.4, 22.4,
4.90–4.84 (m, 1H), 3.71 (dd, J = 5.0 Hz, 1.9 Hz, 2H), 1.66 (d, J = 21.8; GC-HRMS: Calculated for C27H31F2N [M] 407.2419, found
7.0 Hz, 6H); 19F NMR (376 MHz, CDCl3): δ −117.1; 13C NMR 407.2444.
(100 MHz, CDCl3): δ 161.4 (d, JC–F = 244.4 Hz), 144.1, 135.2,
2-(Cyclohex-1-en-1-yl)-1,5-dimethyl-3-(3-nitrophenyl)-1H-indole
134.0, 133.8, 131.9 (d, JC–F = 7.6 Hz), 131.7 (d, JC–F = 3.4 Hz), (5p). Yield: (136 mg, 79%); physical appearance: yellow solid;
128.6, 128.3, 127.9, 127.1, 121.7, 119.6, 119.6, 119.4, 115.3 (d, mp 205–207 °C; TLC Rf 0.4 (10 : 1 petroleum ether : EtOAc);
JC–F = 21.1 Hz), 114.6, 111.6, 87.1, 64.7, 47.7, 21.8; ESI-HRMS: IR (KBr, cm−1): 3355, 2985, 1605, 1445, 1401, 1173, 997; 1H
Calculated for C39H35FNO [M + Na]+ 575.2550, found 575.2567. NMR (400 MHz, CDCl3): δ 8.42 (t, J = 1.8 Hz, 1H), 8.10–8.00 (m,
(E)-3-(4-Fluorophenyl)-2-(3-(trityloxy)prop-1-en-1-yl)-1H-indole 1H), 7.90 (dt, J = 7.7, 1.2 Hz, 1H),7.60–7.46 (m, 1H), 7.25–7.20
(5l). Yield: (147 mg, 57%); physical appearance: off-white (m, 1H), 7.09 (d, J = 8.4 Hz, 1H), 5.98–5.84 (m, 1H), 3.68 (s,
solid; mp 181–186 °C; TLC Rf 0.6 (20 : 1 petroleum ether : 3H), 2.46 (s, 3H), 2.30–2.04 (m, 2H) 1.83–1.21 (m, 6H);
EtOAc); IR (KBr, cm−1): 3455, 2950, 1601, 1492, 1373, 1068, 13C NMR (100 MHz, CDCl3): δ 148.5, 141.3, 138.1, 134.1, 129.3,
990; 1H NMR (400 MHz, CDCl3): δ 8.19 (bs, 1H), 7.62 (d, J = 129.0, 126.3, 123.7, 123.3, 119.9, 118.2, 110.3, 109.4, 30.4, 29.8,
8.0 Hz, 1H), 7.54–7.41 (m, 8H), 7.39–7.09 (m, 14H), 6.87 (d, J = 25.7, 22.8, 21.8, 21.6; GC-HRMS: Calculated for C22H23N2O2
16.3 Hz, 1H), 6.11 (dt, J = 16.1, 5.2 Hz, 1H), 3.82 (dd, J = 5.2, [M + H]+ 347.1754, found 347.1769.
1.8 Hz, 2H); 19F NMR (376 MHz, CDCl3): δ −116.2; 13C NMR
(E)-Triethyl((5-(trityloxy)penta-1,3-dien-2-yl)oxy)silane (14). Yield:
(100 MHz, CDCl3): δ 161.8 (d, JC–F = 245.3 Hz), 144.1, (761 mg, 67%); physical appearance: colorless oil; TLC (neutral
136.1, 131.9, 131.5 (d, JC–F = 7.8 Hz), 130.5 (d, JC–F = 3.0 Hz), alumina) Rf 0.75 (petroleum ether); this compound was uti-
128.6, 128.0, 127.9, 127.1, 125.8, 123.4, 120.4, 120.1, lized immediately upon work-up. IR (KBr, cm−1): 3033, 2912,
1
119.5, 116.6, 115.5 (d, JC–F
64.6; ESI-HRMS: Calculated for C36H28FNO [M
532.2047, found 532.2057.
=
21.3 Hz), 110.7, 87.1, 1612, 1492, 1069; H NMR (400 MHz, CDCl3): δ 7.50–7.41 (m,
+
Na]+ 6H), 7.33–7.19 (m, 9H), 6.28 (dt, J = 15.2 Hz, 4.9 Hz, 1H), 6.07
(dt, J = 15.3 Hz, 4.9 Hz, 1H), 4.32 (s, 2H), 3.68 (dd, J = 5.0,
(E)-3-(4-(tert-Butyl)phenyl)-2-styryl-1H-indole
(5m). Yield: 1.7 Hz, 2H), 0.99 (t, J = 7.9 Hz, 9H), 0.72 (q, J = 7.9 Hz, 6H); 13
C
(103 mg, 57%); physical appearance: off-white solid; mp NMR (100 MHz, CDCl3): δ 154.9, 144.3, 128.8, 128.1, 127.9,
78–83 °C; TLC Rf 0.6 (20 : 1 petroleum ether : EtOAc); IR (KBr, 127.6, 127.1, 95.2, 87.0, 64.2, 6.9, 5.1.
cm−1): 3321, 3025, 2849, 1601, 1492, 1181, 990; 1H NMR
(E)-1-(4-Fluorophenyl)-5-(trityloxy)pent-3-en-2-one (9). Yield:
(400 MHz, CDCl3): δ 8.27 (s, 1H), 7.75 (d, J = 8.0 Hz, 1H), (121 mg, 55%); physical appearance: off-white solid; mp
7.61–7.40 (m, 6H), 7.40–7.25 (m, 6H), 7.18–7.12 (m, 1H), 6.89 139–145 °C; TLC Rf 0.6 (1 : 1 petroleum ether : DCM); IR (KBr,
1
(d, J = 16.5 Hz, 1H), 1.44 (s, 9H); 13C NMR (100 MHz, CDCl3): cm−1): 3059, 2922, 1700, 1601, 1492, 990; H NMR (400 MHz,
δ 149.4, 137.1, 136.6, 132.5, 131.6, 129.8, 128.8, 128.3, 127.7, CDCl3): δ 7.45–7.36 (m, 6H), 7.34–7.21 (m, 9H), 7.20–7.14 (m,
127.1, 126.5, 125.7, 123.6, 120.4, 120.0, 118.8, 118.3, 110.7, 2H), 7.09–7.07 (m, 2H), 6.85 (dt, J = 15.9 Hz, 3.8 Hz, 1H), 6.63
34.7, 31.5; GC-HRMS: Calculated for C26H25N [M]+ 351.1982, (dt, J = 15.9 Hz, 2.2 Hz, 1H), 3.83 (s, 2H), 3.82–3.78 (m, 2H);
found 351.1954.
19F NMR (376 MHz, CDCl3): δ −115.91; 13C NMR (100 MHz,
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CDCl3): δ 197.06, 161.97 (d, JC–F = 245.3 Hz), 144.0, 143.6,
131.1 (d, JC–F = 8.0 Hz), 130.1 (d, JC–F = 3.2 Hz), 128.5, 128.0,
127.4, 127.3, 115.6 (d, JC–F = 21.4 Hz), 87.2, 63.2, 47.0;
ESI-HRMS: Calculated for C30H25FO2 [M + Na]+ 459.1731,
found 459.1747.
Notes and references
1 (a) E. Fischer and F. Jourdan, Ber. Dtsch. Chem. Ges., 1883,
16, 2241–2245; (b) R. B. Van Order and H. G. Lindwall,
Chem. Rev., 1942, 30, 69–96; (c) A. R. Katritzky and
C. A. Drum, in Comprehensive Heterocyclic Chemistry, ed.
A. R. Katritzky and C. W. Rees, Pergamon Press, Oxford,
1984, vol. 1; (d) R. J. Sundberg, Indoles, Academic Press,
London, 1996; (e) J. A. Joule and K. Mills, in Heterocyclic
Chemistry, Wiley, UK, 5th edn, 2010; (f) G. W. Gribble,
J. Chem. Soc., Perkin Trans. 1, 2000, 1045–1075;
(g) D. A. Horton, G. T. Bourne and M. L. Smythe, Chem. Rev.,
2003, 103, 893–930; (h) G. R. Humphrey and J. T. Kuethe,
Chem. Rev., 2006, 106, 2875–2911; (i) K. Krüger (née Alex),
A. Tillack and M. Beller, Adv. Synth. Catal., 2008, 350, 2153–
2167; (j) A. J. Kochanowska-Karamyan and M. T. Hamann,
Chem. Rev., 2010, 110, 4489–4497; (k) S. Cacchi and
G. Fabrizi, Chem. Rev., 2011, 111, PR215–PR283;
(l) D. F. Taber and P. K. Tirunahari, Tetrahedron, 2011, 67,
7195–7210; (m) M. Platon, R. Amardeil, L. Djakovitch and
J.-C. Hierso, Chem. Soc. Rev., 2012, 41, 3929–3968;
(n) M. Inman and C. J. Moody, Chem. Sci., 2013, 4, 29–41.
2 P. C. Fuenfschiling, P. Hoehn and J.-P. Muetz, Org. Process
Res. Dev., 2007, 11, 13–18.
Triethyl(((1E,3E)-1-(4-fluorophenyl)-5-(trityloxy)penta-1,3-dien-2-
yl)oxy)silane (15). Yield: (152 mg, 65%); physical appearance:
colorless oil; TLC (neutral alumina) Rf 0.75 (petroleum ether);
IR (KBr, cm−1): 3052, 2921, 1601, 1492, 1452, 1152; 1H NMR
(400 MHz, CDCl3): δ 7.53–7.49 (m, 7H), 7.36–7.30 (m, 7H),
7.29–7.25 (m, 3H), 7.03–6.96 (m, 2H), 6.39 (dt, J = 15.3 Hz,
1.7 Hz, 1H), 6.20–6.04 (m, 1H), 5.73 (s, 1H), 3.78–3.74 (m, 2H),
0.96 (t, J = 7.9 Hz, 9H), 0.65 (q, J = 8.0 Hz, 6H); 19F NMR
(400 MHz, CDCl3): δ −115.60; 13C NMR (100 MHz, CDCl3):
δ 161.2 (d, JC–F = 245.8 Hz), 149.6 (d, JC–F = 2.1 Hz), 144.2,
132.7 (d, JC–F = 3.6 Hz), 130.3 (d, JC–F = 7.9 Hz), 129.8, 128.7,
127.9, 127.4, 127.1, 114.9 (d, JC–F = 21.3 Hz), 112.1, 87.0, 64.3,
6.8, 5.5; ESI-HRMS: Calculated for C36H39O2FSi [M + Na]+
573.2596, found 573.2602.
(E)-3-(3-(4-Fluorophenyl)-1-isopropyl-1H-indol-2-yl)prop-2-en-1-ol
(16).4 Yield: (17 mg, 62%); physical appearance: yellow gel;
TLC Rf 0.4 (5 : 1 petroleum ether : EtOAc); IR (KBr, cm−1): 3424,
3025, 2926, 1601, 1028; 1H NMR (400 MHz, CDCl3): δ 7.59–7.43
(m, 2H), 7.45–7.35 (m, 2H), 7.21–7.15 (m, 1H), 7.15–7.01 (m,
3H), 6.66 (dt, J = 16.2 Hz, 1.8 Hz, 1H), 5.85 (dt, J = 16.0, 5.0 Hz,
1H), 4.97–4.80 (m, 1H), 4.35–4.16 (m, 2H), 1.66 (d, J = 7.0 Hz,
3 (a) V. K. Tiwari, N. Kamal and M. Kapur, Org. Lett., 2015,
17, 1766–1769; (b) A. P. Kale, G. S. Kumar,
A. R. K. Mangadan and M. Kapur, Org. Lett., 2015, 18,
1324–1327.
6H); 19F NMR (376 MHz, CDCl3):
δ
−116.9; 13C NMR
(100 MHz, CDCl3): δ 161.5 (d, JC–F = 244.8 Hz), 135.5, 135.1,
133.4, 131.9, 131.8, 128.4, 121.8, 119.6, 119.6, 119.5, 115.4,
115.2, 111.7, 63.6, 47.7, 21.7; ESI-HRMS: Calculated for
C20H20FNO [M]+ 309.1523, found 309.1537.
4 (a) A. P. Kale, G. P. Pawar and M. Kapur, Org. Lett., 2012,
14, 1808–1811. For reviews on transition-metal catalyzed
α-arylation of activated C–H bonds, see: (b) M. Miura and
M. Nomura, Top. Curr. Chem., 2002, 219, 211–241;
(c) G. C. Llyod-Jones, Angew. Chem., Int. Ed., 2002, 41, 953–
956; (d) F. Bellina and R. Rossi, Chem. Rev., 2010, 110,
1082–1146; (e) C. C. C. Johansson and T. J. Colacot, Angew.
Chem., Int. Ed., 2010, 49, 676–707; (f) P. No˜vak and
R. Martin, Curr. Org. Chem., 2011, 15, 3233–3262;
(g) S. T. Sivanandan, A. Shaji, I. Ibnusaud,
C. C. C. Johansson Seechurn and T. J. Colacot, Eur. J. Org.
Chem., 2015, 38–49. For literature on arylation of silylenol
ethers see, (h) I. Kuwajima and H. Urabe, J. Am. Chem. Soc.,
1982, 104, 6831–6833; (i) I. Kuwajima and E. Nakamura,
Acc. Chem. Res., 1985, 18, 181–187; ( j) W. P. Su, S. Raders,
J. G. Verkade, X. B. Liao and J. F. Hartwig, Angew. Chem.,
Int. Ed., 2006, 45, 5852–5855; (k) T. Iwama and V. H. Rawal,
Org. Lett., 2006, 8, 5725–5728.
(E)-3-(3-(4-Fluorophenyl)-1-isopropyl-1H-indol-2-yl)acrylaldehyde
(7).8 Yield: (8 mg, 80%); physical appearance: off-white solid;
mp 128–130 °C; TLC Rf 0.6 (5 : 1 petroleum ether : EtOAc);
IR (KBr, cm−1): 2978, 1675, 1536, 1344, 1224, 1122, 840, 745;
1H NMR (500 MHz, CDCl3): δ 9.59 (d, J = 7.5 Hz, 1H), 7.64–7.54
(m, 3H), 7.43–7.32 (m, 3H), 7.23–7.11 (m, 3H), 6.34 (dd, J =
16.2 Hz, 7.5 Hz, 1H), 4.98–5.09 (m, 1H), 1.76 (d, J = 7.0 Hz,
6H); 19F NMR (376 MHz, CDCl3): δ −114.58; 13C NMR
(100 MHz, CDCl3): δ 193.3, 162.3 (d, JC–F = 247.3 Hz), 141.0,
137.5, 131.9 (d, JC–F = 8.0 Hz), 130.4, 129.9 (d, JC–F = 2.9 Hz),
129.6, 128.4, 124.6, 122.8, 121.0, 120.6, 115.9 (d, JC–F = 21.5
Hz), 112.5, 48.3, 29.7, 21.8; ESI-HRMS: Calculated for
C20H19FNO [M + H]+ 308.1445, found 308.1445.
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Acknowledgements
Funding from DST – India (SR/S1/OC-60/2010) and CSIR-India
(02(205)/14/EMR-II) is gratefully acknowledged. A.P.K. and G.S.
K. thank UGC – India and CSIR – India, respectively, for their
Research Fellowships. We thank Central Instrumentation Faci-
lity (CIF), IISERB, for the spectral data and the Director,
IISERB, for funding and infrastructural facilities.
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